These studies are designed to understand the physiological mechanisms that regulate effector cell localization into the liver, which is often a site for metastasis formation. IL-12 and IL-2 are potent immunoregulatory cytokines for natural killer(NK) and T cells, and they induce beneficial antitumor activities in numerous experimental models. The liver, which is often a site for metastasis formation, has been used as a model organ to determine the role of adhesion molecules and endogenous IFNg in the initial recruitment of, and regulatory interactions between, NK and T cells by IL-12 versus IL-2. Daily administration of IL-2 resulted in a progressive increase in NK1.1+ cells, while daily administration of IL-12 caused a rapid increase in NK cells followed by a subsequent decrease coincident with an increase in T cells. The early induction of hepatic NK cells, but not the subsequent T cell infiltrate, by IL-12 was abrogated in IFNg -/- mice, while the recruitment of liver-associated NK cells by IL-2 was not diminished in IFNg -/- mice. The IL-12-induced increase in both hepatic NK and T cells was abrogated by in vivo treatment with anti-VCAM-1 monoclonal antibodies, while treatment with anti-ICAM-1 antibodies caused a decrease only in the IL-12-induced T cell infiltrate. The increase in IL-12-induced hepatic NK cells was maintained in SCID mice, and in lpr/lpr(Fas-) and gld/gld(FasL-) mutant mice. These results demonstrate that NK and T cell recruitment to hepatic parenchyma occurs through different pathways, and that liver-localizing T cells actively eliminate the liver-localizing NK cells by a FAS/FasL dependent pathway. The results also demonstrate that cytokine-mediated biological therapy can induce opposing positive and negative effects that might complicate therapeutic stratagies, and suggest that a better understanding of the ability of IL-2 and IL-12 to induce T and NK cell recruitment to different tumor and organ sites may provide new insight into the success or failure of biological therapy.